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To understand the molecular mechanisms of duodenal-derived serotonin action on osteoblasts, the authors explored its transcriptional mediation in mice. They found that the transcription factor FOXO1 was a crucial determinant of the effects of duodenum-derived serotonin on bone formation. Furthermore, they identified two key FOXO1 complexes in osteoblasts, one with the transcription factor cAMP-responsive element-binding protein 1 (CREB) and another with activating transcription factor 4 (ATF4) that mediate these effects.